The present invention provides methods of using growth hormone secretagogues, prodrugs thereof and pharmaceutically acceptable salts of said secretagogues and said prodrugs, as stimulators of the motility of the gastrointestinal system in patients. More specifically, the present invention provides methods of using compounds of Formula I below as stimulators of the motility of the gastrointestinal system in patients. In addition, the present invention provides methods of treating conditions of impaired gastrointestinal motility, such as gastroesophageal reflux disease, gastroparesis (e.g., as a complication of diabetes), emesis (e.g., that caused by cancer chemotherapy agents), postoperative ileus, constipation (e.g., that associated with the hypomotility phase of irritable bowel syndrome) and colonic pseudo-obstruction. The present invention also provides pharmaceutical compositions and kits for the above uses.
Gastrointestinal (GI) motility is a coordinated neuromuscular process that transports nutrients through the digestive system. C. Scarpignato, Dig. Dis. 15: 112 (1997). Impaired GI motility, which may be involved in gastroesophageal reflux disease, gastroparesis (e.g., diabetic and postsurgical), irritable bowel syndrome and constipation, is one of the largest health care burdens of industralized nations. S. D. Feighner et al., Science 284: 2184-2188 (Jun. 25, 1999). Impaired GI motility can also lead to emesis (e.g., that caused by cancer chemotherapy agents), postoperative ileus and colonic pseudo-obstruction.
Very few compounds are known in the art to be useful for treating impaired GI motility. For example, PROPULSID(copyright) which contains cisapride monohydrate is an oral gastrointestinal agent (see U.S. Pat. No. 4,962,115). It is indicated for the symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease. Other prokinetic agents include, for example, metoclopramide, erythromycin, domperidone, ondansetron, tropisetron, mosapride and itopride. However, these therapeutic regimens suffer from numerous problems. For instance, PROPULSID(copyright) was recently removed from the market due to its potential to induce cardiac arrhythmias. A more effective, physiological way to stimulate GI motility would be highly desirable.
Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body: (1) increased rate of protein synthesis in all cells of the body; (2) decreased rate of carbohydrate utilization in cells of the body; and (3) increased mobilization of free fatty acids and use of fatty acids for energy. As is known to those skilled in the art, the known and potential uses of growth hormone are varied and multitudinous. See xe2x80x9cHuman Growth Hormone,xe2x80x9d Strobel and Thomas, Pharmacological Reviews, 46, pg. 1-34 (1994). Also, these varied uses of growth hormone are summarized in International Patent Application, Publication Number WO 97/24369.
Various ways are known to release growth hormone (see Recent Progress in Hormone Research, vol. 52, pp. 215-245 (1997); and Front Horm Res. Basel, Karger, vol. 24, pp. 152-175 (1999)). For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase secretion of growth hormone releasing factor (GRF) or ghrelin (see Nature, vol. 402, pp. 656-660 (Dec. 9, 1999)), or all of these.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering GRF, IGF-I or a peptidyl compound which stimulated growth hormone production and/or release. In any case, the peptidyl nature of the compound necessitated that it be administered by injection. Initially, the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection. In addition, administration of exogenous growth hormone may result in side-effects, including edema, and does not correlate with the pulsatile release seen in the endogenous release of growth hormone.
Certain compounds have been developed which stimulate the release of endogenous growth hormone. Peptides which are known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone and its analogs, the growth hormone releasing peptides, GHRP-6 and GHRP-1 (described in U.S. Pat. No. 4,411,890; International Patent Application, Publication No. WO 89/07110; and International Patent Application, Publication No. WO 89/07111), and GHRP-2 (described in International Patent Application, Publication No. WO 93/04081), as well as hexarelin (J. Endocrinol. Invest., 15 (Suppl. 4): 45 (1992)). Other compounds possessing growth hormone secretagogue activity are disclosed in the following International Patent Applications (listed by Publication Nos.), issued U.S. Patents and published European Patent Applications: WO 98/46569, WO 98/51687, WO 98/58947, WO 98/58949, WO 98/58950, WO 99/08697, WO 99/09991, WO 95/13069, U.S. Pat. Nos. 5,492,916, 5,494,919, WO 95/14666, WO 94/19367, WO 94/13696, WO 94/11012, U.S. Pat. No. 5,726,319, WO 95/11029, WO 95/17422, WO 95/17423, WO 95/34311, WO 96/02530, WO 96/22996, WO 96/22997, WO 96/24580, WO 96/24587, U.S. Pat. No. 5,559,128, WO 96/32943, WO 96/33189, WO 96/15148, WO 96/38471, WO 96/35713, WO 97/00894, WO 97/07117, WO 97/06803, WO 97/11697, WO 97/15573, WO 97/22367, WO 97/23508, WO 97/22620, WO 97/22004, WO 97/21730, WO 97/24369, U.S. Pat. No. 5,663,171, WO 97/34604, WO 97/36873, WO 97/40071, WO 97/40023, WO 97/41878, WO 97/41879, WO 97/46252, WO 97/44042, WO 97/38709, WO 98/03473, WO 97/43278, U.S. Pat. Nos. 5,721,251, 5,721,250, WO 98/10653, U.S. Pat. Nos. 5,919,777, 5,830,433 and EP 0995748.
In addition, the following growth hormone secretagogues are known in the art: MK-0677, L-162752 and L-163022 (Merck); NN703 and ipamorelin (Novo Nordisk); hexarelin (Pharmacia and Upjohn); GPA-748 (KP102, GHRP-2) (American Home Products); and LY444711 (Eli Lilly). The following agents that stimulate GH release via GHRH/GRF receptor (including GHRH/GRF derivatives, analogs and mimetics) are known in the art: Geref (Ares/Serono); GHRH (1-44) (BioNebraska); Somatorelin (GRF 1-44) (Fujisawa/ICN); and ThGRF (Theratechnologies).
Endocrine Reviews 18(5): 621-645 (1997) provides an overview of peptidomimetic regulation of growth hormone secretion by growth hormone secretagogues. Horm. Res. 1999; 51(suppl 3):16-20 (1999), examines the clinical and experimental effects of growth hormone secretagogues on various organ systems. Drug Discovery Today, Vol. 4, No. 11, November 1999; and TEM Vol. 10, No. 1, 1999, disclose potential therapeutic applications of growth hormone secretagogues, including their use in treating growth hormone disorders such as growth hormone deficiency (GHD), age-related conditions, obesity and catabolic conditions, and their use in sleep enhancement.
International Patent Applications, Publication Nos. WO 97/24369 and WO 98/58947 disclose that certain growth hormone secretagogues are useful for the treatment or prevention of osteoporosis, congestive heart failure, frailty associated with aging, obesity; accelerating bone fracture repair, attenuating protein catabolic response after a major operation, reducing cachexia and protein loss due to chronic illness, accelerating wound healing or accelerating the recovery of burn patients or patients having undergone major surgery; improving muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis or renal homeostasis. Published European patent application 0995748 discloses that certain dipeptide growth hormone secretagogues are useful for the treatment or prevention of musculoskeletal frailty, including osteoporosis.
The administration of a growth hormone secretagogue is also known to enhance the quality of sleep, which is disclosed in International Patent Application, Publication No. WO 97/24369. A growth hormone secretagogue can be administered to a patient having or at risk of having one or more of the conditions or symptoms recited above. Commonly assigned U.S. nonprovisional patent application Ser. No. 09/290985, filed Apr. 13, 1999, discloses pharmaceutical compositions comprising certain xcex23 adrenergic agonists and growth hormone secretagogues or growth hormone, and their use for treating diabetes, obesity, hyperglycemia, frailty associated with obesity or frailty associated with aging, and for enhancing the quality of sleep in a mammal. International Patent Application, Publication No. WO 98/58949, discloses the treatment of insulin resistance with certain growth hormone secretagogues.
Abstract OR4-5 from The Endocrine Society 81st Annual Meeting (Jun. 12-15, 1999), San Diego, Calif., discloses that growth hormone (GH) therapy resulted in marked clinical improvement in patients with active Crohn""s disease (regional inflammation of the intestines).
S. D. Feighner et al., Science 284: 2184-2188 (Jun. 25, 1999), discloses that a heterotrimeric guanosine triphosphate-binding protein (G protein)-coupled receptor for motilin (a 22-amino acid peptide hormone expressed throughout the gastrointestinal tract of humans and other species) was isolated from the human stomach, and that its amino acid sequence was found to be 52 percent identical to the human receptor for growth hormone secretagogues.
The present invention provides a method of stimulating the motility of the gastrointestinal system in a patient which comprises administering to the patient a gastrointestinal motility stimulating effective amount of a growth hormone secretagogue.
More particularly, it provides such method wherein the growth hormone secretagogue is an orally active growth hormone secretagogue. Even more particularly, it provides such method wherein the growth hormone secretagogue is orally administered.
More particularly, it provides such method wherein the growth hormone secretagogue is a non-peptidyl growth hormone secretagogue.
More particularly, it provides such method wherein the patient is a human.
The present invention provides a method of stimulating the motility of the gastrointestinal system in a patient which comprises administering to the patient a gastrointestinal motility stimulating effective amount of a Compound of the Formula I: 
or a stereoisomeric mixture thereof, diastereomerically enriched, diastereomerically pure, enantiomerically enriched or enantiomerically pure isomer thereof, or a prodrug of such compound, mixture or isomer thereof, or a pharmaceutically acceptable salt of the compound, mixture, isomer or prodrug, or a tautomer thereof, wherein
HET is a heterocyclic moiety selected from the group consisting of 
d is 0, 1 or 2;
e is 1 or 2;
f is 0or 1;
n and w are 0, 1 or 2, provided that n and w cannot both be 0 at the same time;
Y2 is oxygen or sulfur;
A is a divalent radical, where the left hand side of the radical as shown below is connected to Cxe2x80x3 and the right hand side of the radical as shown below is connected to Cxe2x80x2, selected from the group consisting of
xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94NR2, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR2, xe2x80x94NR2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94S(O)2xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94S(O)2xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94C(O)xe2x80x94NR2, xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94S(O)2xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R9R10)xe2x80x94, C(O)xe2x80x94Nxe2x95x90C(R11)xe2x80x94NR2xe2x80x94, xe2x80x94C(O)xe2x80x94NR2xe2x80x94C(R11)xe2x95x90Nxe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR12xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR12xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR12xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94NR2xe2x80x94C(R11)xe2x95x90Nxe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94N(R12)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94NR12xe2x80x94Nxe2x95x90C(R11)xe2x80x94NR2xe2x80x94C(O)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94S(O)2xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94S(O)2xe2x80x94NR2xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94C(R9R10)xe2x80x94S(O)2xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94S(O)2xe2x80x94, xe2x80x94Oxe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94Oxe2x80x94, xe2x80x94C(R9R10)xe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94, xe2x80x94C(O)xe2x80x94C(R9R10)xe2x80x94C(R9R10)xe2x80x94 and xe2x80x94C(R9R10)xe2x80x94NR2xe2x80x94S(O)2xe2x80x94NR2xe2x80x94;
Q is a covalent bond or CH2;
W is CH or N;
X is CR9R10, Cxe2x95x90CH2 or Cxe2x95x90O;
Y is CR9R10, O or NR2;
Z is Cxe2x95x90O, Cxe2x95x90S or S(O)2;
G1 is hydrogen, halo, hydroxy, nitro, amino, cyano, phenyl, carboxyl, xe2x80x94CONH2, xe2x80x94(C1-C4)alkyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, xe2x80x94(C1-C4)alkoxy optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, xe2x80x94(C1-C4)alkylthio, phenoxy, xe2x80x94COO(C1-C4)alkyl, N,N-di-(C1-C4)alkylamino, xe2x80x94(C2-C6)alkenyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, xe2x80x94(C2-C6)alkynyl optionally independently substituted with one or more phenyl, one or more halogens or one or more hydroxy groups, xe2x80x94(C3-C6)cycloalkyl optionally independently substituted with one or more (C1-C4)alkyl groups, one or more halogens or one or more hydroxy groups, xe2x80x94(C1-C4)alkylamino carbonyl or di-(C1-C4)alkylamino carbonyl; G2 and G3 are each independently selected from the group consisting of hydrogen, halo, hydroxy, xe2x80x94(C1-C4)alkyl optionally independently substituted with one to three halo groups and xe2x80x94(C1-C4)alkoxy optionally independently substituted with one to three halo groups;
R1 is hydrogen, xe2x80x94CN, xe2x80x94(CH2)qN(X6)C(O)X6, xe2x80x94(CH2)qN(X6)C(O)(CH2)t-A1, xe2x80x94(CH2)qN(X6)S(O)2(CH2)t-A1, xe2x80x94(CH2)qN(X6)S(O)2X6, xe2x80x94(CH2)qN(X6)C(O)N(X6)(CH2)t-A1, xe2x80x94(CH2)qN(X6)C(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(CH2)tA1, xe2x80x94(CH2)qC(O)OX6, xe2x80x94(CH2)qC(O)O(CH2)t-A1, xe2x80x94(CH2)qOX6, xe2x80x94(CH2)qOC(O)X6, xe2x80x94(CH2)qOC(O)(CH2)t-A1, xe2x80x94(CH2)qOC(O)N(X6)(CH2)t-A1, xe2x80x94(CH2)qOC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)X6, xe2x80x94(CH2)qC(O)(CH2)t-A1, xe2x80x94(CH2)qN(X6)C(O)OX6, xe2x80x94(CH2)qN(X6)S(O)2N(X6)(X6), xe2x80x94(CH2)qS(O)X6, xe2x80x94(CH2)qS(O)m(CH2)t-A1, xe2x80x94(C1-C10)alkyl, xe2x80x94(CH2)t-A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)t-A1 or xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94(C3-C7)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro groups;
Y1 is O, S(O)m, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94N(X6)C(O)xe2x80x94, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)N(X6)xe2x80x94 or xe2x80x94OC(O)xe2x80x94;
q is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
said (CH2)q group and (CH2)t group in the definition of R1 are optionally independently substituted with hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro groups or 1 or 2 (C1-C4)alkyl groups;
R1A is selected from the group consisting of hydrogen, F, Cl, Br, I, (C1-C6)alkyl, phenyl(C1-C3)alkyl, pyridyl(C1-C3)alkyl, thiazolyl(C1-C3)alkyl and thienyl(C1-C3)alkyl, provided that R1A is not F, Cl, Br or I when a heteroatom is vicinal to Cxe2x80x3;
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1;
where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxy, xe2x80x94C(O)OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94N(X6)(X6), xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)A1, xe2x80x94C(O)(X6), CF3, CN or 1, 2 or 3 independently selected halo groups;
R3 is selected from the group consisting of A1, (C1-C10)alkyl, xe2x80x94(C1-C6)alkyl-A1, xe2x80x94(C1-C6)alkyl-(C3-C7)cycloalkyl, xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C1-C5)alkyl, xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C0-C5)alkyl-A1 and xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C1-C5)alkyl-(C3-C7)cycloalkyl;
where the alkyl groups in the definition of R3 are optionally substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1, 2, 3, 4 or 5 independently selected halo groups or 1, 2 or 3 independently selected xe2x80x94OX3 groups;
X1 is O, S(O)m, xe2x80x94N(X2)C(O)xe2x80x94, xe2x80x94C(O)N(X2)xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94CX2xe2x95x90CX2xe2x80x94, xe2x80x94N(X2)C(O)Oxe2x80x94, xe2x80x94OC(O)N(X2)xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94;
R4 is hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl, or R4 is taken together with R3 and the carbon atom to which they are attached and form (C5-C7)cycloalkyl, (C5-C7)cycloalkenyl, a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, or is a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, fused to a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
X4 is hydrogen or (C1-C6)alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached and form a five to seven membered ring;
R6 is a bond or is 
where a and b are each independently 0, 1, 2 or 3;
X5 and X5a are each independently selected from the group consisting of hydrogen, CF3, A1 and optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX2, (C3-C7)cycloalkyl, xe2x80x94N(X2)(X2) and xe2x80x94C(O)N(X2)(X2);
or the carbon bearing X5 or X5a forms one or two alkylene bridges with the nitrogen atom bearing R7 and R8 wherein each alkylene bridge contains 1 to 5 carbon atoms, provided that when one alkylene bridge is formed then only one of X5 or X5a is on the carbon atom and only one of R7 or R8 is on the nitrogen atom and further provided that when two alkylene bridges are formed then X5 and X5a cannot be on the carbon atom and R7 and R8 cannot be on the nitrogen atom;
or X5 is taken together with X5a and the carbon atom to which they are attached and form a partially saturated or fully saturated 3- to 7-membered ring, or a partially saturated or fully saturated 4- to 8-membered ring having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen;
or X5 is taken together with X5a and the carbon atom to which they are attached and form a bicyclic ring system consisting of a partially saturated or fully saturated 5- or 6-membered ring, optionally having 1 or 2 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
Z1 is a bond, O or Nxe2x80x94X2, provided that when a and b are both 0 then Z1 is not Nxe2x80x94X2 or O;
or R6 is xe2x80x94(CRaRb)a-E-(CRaRb)bxe2x80x94, where the xe2x80x94(CRaRb)a group is attached to the carbonyl carbon of the amide group of the compound of formula I and the xe2x80x94(CRaRb)b group is attached to the terminal nitrogen atom of the compound of Formula I;
E is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 or an aromatic moiety selected from 
said aromatic moiety in the definition of E optionally substituted with up to three halo, hydroxy, xe2x80x94N(Rc)(Rc), (C1-C6)alkyl or (C1-C6)alkoxy; Ra and Rb are, for each occurrence, independently hydrogen, (C1-C6)alkyl, trifluoromethyl, phenyl or monosubstituted (C1-C6)alkyl where the substituents are imidazolyl, naphthyl, phenyl, indolyl, p-hydroxyphenyl, xe2x80x94ORc, S(O)mRc, C(O)ORc, (C3-C7)cycloalkyl, xe2x80x94N(Rc)(Rc), xe2x80x94C(O)N(Rc)(Rc), or Ra or Rb may independently be joined to one or both of R7 or E (where E is other than O, S or xe2x80x94CHxe2x95x90CHxe2x80x94) to form an alkylene bridge between the terminal nitrogen and the alkyl portion of the Ra or Rb and the R7 or E group, wherein the bridge contains 1 to 8 carbon atoms; or Ra and Rb may be joined to one another to form a (C3-C7)cycloalkyl;
Rc, for each occurrence, is independently hydrogen or (C1-C6)alkyl; a and b are independently 0, 1, 2 or 3, with the proviso that if E is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94, b is other than 0 or 1 and with the further proviso that if E is xe2x80x94CHxe2x95x90CHxe2x80x94, b is other than 0;
R7 and R8 are each independently hydrogen or optionally substituted (C1-C6)alkyl;
where the optionally substituted (C1-C6)alkyl in the definition of R7 and R8 is optionally independently substituted with A1, xe2x80x94C(O)Oxe2x80x94(C1-C6)alkyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 xe2x80x94Oxe2x80x94C(O)(C1-C10)alkyl groups or 1 to 3 (C1-C6)alkoxy groups; or
R7 and R8 can be taken together to form xe2x80x94(CH2)r-L-(CH2)rxe2x80x94;
where L is C(X2)(X2), S(O)m or N(X2);
R9 and R10 are each independently selected from the group consisting of hydrogen, fluoro, hydroxy and (C1-C5)alkyl optionally independently substituted with 1-5 halo groups;
R11 is selected from the group consisting of (C1-C5)alkyl and phenyl optionally substituted with 1-3 substituents each independently selected from the group consisting of (C1-C5)alkyl, halo and (C1-C5)alkoxy;
R12 is selected from the group consisting of (C1-C5)alkylsulfonyl, (C1-C5)alkanoyl and (C1-C5)alkyl where the alkyl portion is optionally independently substituted by 1-5 halo groups;
A1 for each occurrence is independently selected from the group consisting of (C5-C7)cycloalkenyl, phenyl, a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen and a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, on one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94S(O)2N(X6)(X6), xe2x80x94N(X6)S(O)2-phenyl, xe2x80x94N(X6)S(O)2X6, xe2x80x94CONX11X12, xe2x80x94S(O)2NX11X12, xe2x80x94NX6S(O)2X12, xe2x80x94NX6CONX11X12, xe2x80x94NX6S(O)2NX11X12, xe2x80x94NX6C(O)X12, imidazolyl, thiazolyl and tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halo groups, 1 to 3 hydroxy groups, 1 to 3 (C1-C10)alkanoyloxy groups or 1 to 3 (C1-C6)alkoxy groups;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 group is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)r-L1-(CH2)rxe2x80x94;
L1 is C(X2)(X2), O, S(O)m or N(X2);
r for each occurrence is independently 1, 2 or 3;
X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halo groups or 1-3 OX3 groups;
X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
X6 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenated cycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently mono- or di-substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester or 1H-tetrazol-5-yl; or
when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7 as a ring member;
X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxy;
m for each occurrence is independently 0, 1 or 2;
with the provisos that:
1) X6 and X12 cannot be hydrogen when attached to C(O) or S(O)2 in the form C(O)X6, C(O)X12, S(O)2X6 or S(O)2X12; and
2) when R6 is a bond then L is N(X2) and each r in the definition xe2x80x94(CH2)r-L-(CH2)rxe2x80x94 is independently 2 or 3.
More preferably, the present invention provides such method wherein the compound is of the structural formula below, which is designated herein as Formula I-A 
a racemic-diastereomeric mixture or an optical isomer of said compound or a pharmaceutically-acceptable salt or prodrug thereof, or a tautomer thereof, wherein
f is 0;
n is 0 and w is 2, or n is 1 and w is 1, or n is 2 and w is 0;
Y is oxygen or sulfur;
R1 is hydrogen, xe2x80x94CN, xe2x80x94(CH2)qN(X6)C(O)X6, xe2x80x94(CH2)qN(X6)C(O)(CH2)t-A1, xe2x80x94(CH2)qN(X6)S(O)2(CH2)t-A1, xe2x80x94(CH2)qN(X6)S(O)2X6, xe2x80x94(CH2)qN(X6)C(O)N(X6)(CH2)t-A1, xe2x80x94(CH2)qN(X6)C(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)N(X6)(CH2)tA1, xe2x80x94(CH2)qC(O)OX6, xe2x80x94(CH2)qC(O)O(CH2)t-A1, xe2x80x94(CH2)qOX6, xe2x80x94(CH2)qOC(O)X6, xe2x80x94(CH2)qOC(O)(CH2)t-A1, xe2x80x94(CH2)qOC(O)N(X6)(CH2)t-A1, xe2x80x94(CH2)qOC(O)N(X6)(X6), xe2x80x94(CH2)qC(O)X6, xe2x80x94(CH2)qC(O)(CH2)t-A1, xe2x80x94(CH2)qN(X6)C(O)OX6, xe2x80x94(CH2)qN(X6)S(O)2N(X6)(X6), xe2x80x94(CH2)qS(O)X6, xe2x80x94(CH2)qS(O)m(CH2)t-A1, xe2x80x94(C1-C10)alkyl, xe2x80x94(CH2)t-A1, xe2x80x94(CH2)qxe2x80x94(C3-C7)cycloalkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(C1-C6)alkyl, xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)t-A1 or xe2x80x94(CH2)qxe2x80x94Y1xe2x80x94(CH2)txe2x80x94(C3-C7)cycloalkyl;
where the alkyl and cycloalkyl groups in the definition of R1 are optionally substituted with (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl or 1, 2 or 3 fluoro;
Y1 is O, S(O)m, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94N(X6)C(O)xe2x80x94, xe2x80x94C(O)NX6xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)N(X6)xe2x80x94 or xe2x80x94OC(O)xe2x80x94;
q is 0, 1, 2, 3 or 4;
t is 0, 1, 2 or 3;
said (CH2)q group and (CH2)t group may each be optionally substituted with hydroxyl, (C1-C4)alkoxy, carboxyl, xe2x80x94CONH2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94CO2(C1-C4)alkyl ester, 1H-tetrazol-5-yl, 1, 2 or 3 fluoro, or 1 or 2 (C1-C4)alkyl;
R2 is hydrogen, (C1-C8)alkyl, xe2x80x94(C0-C3)alkyl-(C3-C8)cycloalkyl, xe2x80x94(C1-C4)alkyl-A1 or A1;
where the alkyl groups and the cycloalkyl groups in the definition of R2 are optionally substituted with hydroxyl, xe2x80x94C(O)OX6, xe2x80x94C(O)N(X8)(X6), xe2x80x94N(X6)(X6), xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)A1, xe2x80x94C(O)(X6), CF3, CN or 1, 2 or 3 halogen;
R3 is A1, (C1-C10)alkyl, xe2x80x94(C1-C6)alkyl-A1, xe2x80x94(C1-C6)alkyl-(C3-C7)cycloalkyl, xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C1-C5)alkyl, xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C0-C5)alkyl-A1 or xe2x80x94(C1-C5)alkyl-X1xe2x80x94(C1-C5)alkyl-(C3-C7)cycloalkyl;
where the alkyl groups in the definition of R3 are optionally substituted with, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1, 2, 3, 4 or 5 halogens, or 1, 2 or 3 OX3;
X1 is O, S(O)m, xe2x80x94N(X2)C(O)xe2x80x94, xe2x80x94C(O)N(X2)xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94CX2xe2x95x90CX2xe2x80x94, xe2x80x94N(X2)C(O)Oxe2x80x94, xe2x80x94OC(O)N(X2)xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94;
R4 is hydrogen, (C1-C6)alkyl or (C3-C7)cycloalkyl;
X4 is hydrogen or (C1-C6)alkyl or X4 is taken together with R4 and the nitrogen atom to which X4 is attached and the carbon atom to which R4 is attached and form a five to seven membered ring;
R6 is a bond or is 
where a and b are independently 0, 1, 2 or 3;
X5 and X5a are each independently selected from the group consisting of hydrogen, trifluoromethyl, A1 and optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl in the definition of X5 and X5a is optionally substituted with a substituent selected from the group consisting of A1, OX2, xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX2, (C3-C7)cycloalkyl, xe2x80x94N(X2)(X2) and xe2x80x94C(O)N(X2)(X2);
R7 and R8 are independently hydrogen or optionally substituted (C1-C6)alkyl;
where the optionally substituted (C1-C6)alkyl in the definition of R7 and R8 is optionally independently substituted with A1, xe2x80x94C(O)Oxe2x80x94(C1-C6)alkyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 xe2x80x94Oxe2x80x94C(O)(C1-C10)alkyl or 1 to 3 (C1-C6)alkoxy; or
R7 and R8 can be taken together to form xe2x80x94(CH2)r-L-(CH2)rxe2x80x94;
where L is C(X2)(X2), S(O)m or N(X2);
A1 in the definition of R1 is a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 in the definition of R2, R3, R6, R7 and R8 is independently (C5-C7)cycloalkenyl, phenyl or a partially saturated, fully saturated or fully unsaturated 4- to 8-membered ring optionally having 1 to 4 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen, a bicyclic ring system consisting of a partially saturated, fully unsaturated or fully saturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen, fused to a partially saturated, fully saturated or fully unsaturated 5- or 6-membered ring, optionally having 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, sulfur and oxygen;
A1 for each occurrence is independently optionally substituted, in one or optionally both rings if A1 is a bicyclic ring system, with up to three substituents, each substituent independently selected from the group consisting of F, Cl, Br, I, OCF3, OCF2H, CF3, CH3, OCH3, xe2x80x94OX6, xe2x80x94C(O)N(X6)(X6), xe2x80x94C(O)OX6, oxo, (C1-C6)alkyl, nitro, cyano, benzyl, xe2x80x94S(O)m(C1-C6)alkyl, 1H-tetrazol-5-yl, phenyl, phenoxy, phenylalkyloxy, halophenyl, methylenedioxy, xe2x80x94N(X6)(X6), xe2x80x94N(X6)C(O)(X6), xe2x80x94S(O)2N(X6)(X6), xe2x80x94N(X6)SO2-phenyl, xe2x80x94N(X6)S(O)2X6, xe2x80x94CONX11X12, xe2x80x94S(O)2NX11X12, xe2x80x94NX6S(O)2X12, xe2x80x94NX6CONX11X12, xe2x80x94NX6S(O)2NX11X12, xe2x80x94NX6C(O)X12, imidazolyl, thiazolyl or tetrazolyl, provided that if A1 is optionally substituted with methylenedioxy then it can only be substituted with one methylenedioxy;
where X11 is hydrogen or optionally substituted (C1-C6)alkyl;
the optionally substituted (C1-C6)alkyl defined for X11 is optionally independently substituted with phenyl, phenoxy, (C1-C6)alkoxycarbonyl, xe2x80x94S(O)m(C1-C6)alkyl, 1 to 5 halogens, 1 to 3 hydroxy, 1 to 3 (C1-C10)alkanoyloxy or 1 to 3 (C1-C6)alkoxy;
X12 is hydrogen, (C1-C6)alkyl, phenyl, thiazolyl, imidazolyl, furyl or thienyl, provided that when X12 is not hydrogen, the X12 is optionally substituted with one to three substituents independently selected from the group consisting of Cl, F, CH3, OCH3, OCF3 and CF3;
or X11 and X12 are taken together to form xe2x80x94(CH2)r-L1-(CH2)rxe2x80x94;
where L1 is C(X2)(X2), O, S(O)m or N(X2);
r for each occurrence is independently 1, 2 or 3;
X2 for each occurrence is independently hydrogen, optionally substituted (C1-C6)alkyl, or optionally substituted (C3-C7)cycloalkyl, where the optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X2 are optionally independently substituted with xe2x80x94S(O)m(C1-C6)alkyl, xe2x80x94C(O)OX3, 1 to 5 halogens or 1-3 OX3;
X3 for each occurrence is independently hydrogen or (C1-C6)alkyl;
X6 is independently hydrogen, optionally substituted (C1-C6)alkyl, (C2-C6)halogenated alkyl, optionally substituted (C3-C7)cycloalkyl, (C3-C7)-halogenatedcycloalkyl, where optionally substituted (C1-C6)alkyl and optionally substituted (C3-C7)cycloalkyl in the definition of X6 is optionally independently substituted by 1 or 2 (C1-C4)alkyl, hydroxyl, (C1-C4)alkoxy, carboxyl, CONH2, xe2x80x94S(O)m(C1-C6)alkyl, carboxylate (C1-C4)alkyl ester, or 1H-tetrazol-5-yl; or when there are two X6 groups on one atom and both X6 are independently (C1-C6)alkyl, the two (C1-C6)alkyl groups may be optionally joined and, together with the atom to which the two X6 groups are attached, form a 4- to 9-membered ring optionally having oxygen, sulfur or NX7;
X7 is hydrogen or (C1-C6)alkyl optionally substituted with hydroxyl; and
m for each occurrence is independently 0, 1 or 2;
with the proviso that:
X6 and X12 cannot be hydrogen when it is attached to C(O) or SO2 in the form C(O)X6, C(O)X12, SO2X6 or SO2X12; and
when R6 is a bond then L is N(X2) and each r in the definition xe2x80x94(CH2)r-L-(CH2)rxe2x80x94 is independently 2 or 3.
More preferably, the present invention provides such method wherein the compound is 2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide, a prodrug thereof or a pharmaceutically acceptable salt of the compound or the prodrug. Even more preferably, the present invention provides such method wherein the compound is 2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide, L-tartrate.
Also, more preferably, the present invention provides such method wherein the compound is 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of the compound or the prodrug. Even more preferably, the present invention provides such method wherein the compound is the (L)-(+)-tartaric acid salt of 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide.
Also, more preferably, the present invention provides such method wherein the compound is 2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of the compound or the prodrug. Even more preferably, the present invention provides such method wherein the compound is the (L)-(+)-tartaric acid salt of 2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoroethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide.
The present invention provides such method which further comprises administering a prokinetic agent. More particularly, the present invention provides such method wherein the prokinetic agent is selected from the group consisting of cisapride monohydrate, metoclopramide, erythromycin, domperidone, ondansetron, tropisetron, mosapride and itopride.
The present invention provides such method which further comprises administering a recombinant growth hormone or a growth hormone secretagogue selected from the group consisting of GHRP-6, GHRP-1, GHRP-2, growth hormone releasing factor, an analog of growth hormone releasing factor, IGF-I and IGF-II.
In addition, the present invention provides a method of stimulating gastrointestinal transit in a patient which comprises administering to the patient a gastrointestinal transit stimulating effective amount of a growth hormone secretagogue.
More particularly, the present invention provides such method wherein the growth hormone secretagogue is an orally active growth hormone secretagogue. Even more particularly, the present invention provides such method wherein the growth hormone secretagogue is orally administered.
More particularly, the present invention provides such method wherein the growth hormone secretagogue is a non-peptidyl growth hormone secretagogue.
More particularly, the present invention provides such method wherein the patient is a human.
The present invention provides a method of stimulating gastrointestinal transit in a patient which comprises administering to the patient a gastrointestinal transit stimulating effective amount of a compound of the Formula I, wherein the variables are as defined above. More preferably, the present invention provides such method wherein the compound is of the Formula I-A wherein the variables are as defined above.
Even more preferably, the present invention provides such method wherein the compound is selected from the following: 2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; 2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide, L-tartrate; 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; the (L)-(+)-tartaric acid salt of 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide; 2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and the (L)-(+)-tartaric acid salt of 2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide.
The present invention provides such method which further comprises administering a prokinetic agent. More particularly, the present invention provides such method wherein the prokinetic agent is selected from the group consisting of cisapride monohydrate, metoclopramide, erythromycin, domperidone, ondansetron, tropisetron, mosapride and itopride.
The present invention provides such method which further comprises administering a recombinant growth hormone or a growth hormone secretagogue selected from the group consisting of GHRP-6, GHRP-1, GHRP-2, growth hormone releasing factor, an analog of growth hormone releasing factor, IGF-I and IGF-II.
In addition, the present invention provides a method for treating a condition selected from the group consisting of gastroesophageal reflux disease, gastroparesis, postoperative ileus, emesis, constipation and colonic pseudo-obstruction in a patient which comprises administering to the patient a condition treating effective amount of a growth hormone secretagogue. More particularly, the present invention provides such method wherein the condition is gastroesophageal reflux disease, gastroparesis, postoperative ileus or emesis.
More particularly, the present invention provides such method wherein the growth hormone secretagogue is an orally active growth hormone secretagogue. Even more particularly, the present invention provides such method wherein the growth hormone secretagogue is orally administered.
More particularly, the present invention provides such method wherein the growth hormone secretagogue is a non-peptidyl growth hormone secretagogue.
More particularly, the present invention provides such method wherein the patient is a human.
The present invention provides a method for treating a condition selected from the group consisting of gastroesophageal reflux disease, gastroparesis, postoperative ileus, emesis, constipation and colonic pseudo-obstruction in a patient which comprises administering to the patient a condition treating effective amount of a compound of the Formula I, wherein the variables are as defined above. More preferably, the present invention provides such method wherein the compound is of the Formula I-A.
Even more preferably, the present invention provides such method wherein the compound is selected from the following: 2-amino-N-(2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl)-isobutyramide, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; 2-amino-N-[2-(3a-(R)-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(R)-benzyloxymethyl-2-oxo-ethyl]-isobutyramide, L-tartrate; 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydro-pyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; the (L)-(+)-tartaric acid salt of 2-amino-N-(1-(R)-(2,4-difluoro-benzyloxymethyl)-2-oxo-2-(3-oxo-3a-(R)-pyridin-2-ylmethyl)-2-(2,2,2-trifluoro-ethyl)-2,3,3a,4,6,7-hexahydropyrazolo-[4,3-c]pyridin-5-yl)-ethyl)-2-methyl-propionamide; 2-amino-N-{1(R)-benzyloxymethyl-2-[1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl]-2-oxo-ethyl}-2-methyl-propionamide, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug; and the (L)-(+)-tartaric acid salt of 2-amino-N-(1(R)-benzyloxymethyl-2-(1,3-dioxo-8a(S)-pyridin-2-ylmethyl-2-(2,2,2-trifluoro-ethyl)-hexahydro-imidazo[1,5-a]pyrazin-7-yl)-2-oxo-ethyl)-2-methyl-propionamide.
The present invention provides such method which further comprises administering a prokinetic agent. More particularly, the present invention provides such method wherein the prokinetic agent is selected from the group consisting of cisapride monohydrate, metoclopramide, erythromycin, domperidone, ondansetron, tropisetron, mosapride and itopride.
The present invention provides such method which further comprises administering a recombinant growth hormone or a growth hormone secretagogue selected from the group consisting of GHRP-6, GHRP-1, GHRP-2, growth hormone releasing factor, an analog of growth hormone releasing factor, IGF-I and IGF-II.
The present invention provides a pharmaceutical composition comprising a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug, or a tautomer thereof, as defined above; and an additional compound useful to treat a condition selected from the group consisting of gastroesophageal reflux disease, gastroparesis, postoperative ileus, emesis, constipation and colonic pseudo-obstruction. More particularly, the present invention provides such composition wherein the condition is gastroesophageal reflux disease, gastroparesis, postoperative ileus or emesis.
The present invention provides such composition wherein the additional compound is a prokinetic agent. More particularly, the present invention provides such composition wherein the prokinetic agent is selected from the group consisting of cisapride monohydrate, metoclopramide, erythromycin, domperidone, ondansetron, tropisetron, mosapride and itopride.
Finally, the present invention provides a kit for treating a condition selected from the group consisting of gastroesophageal reflux disease, gastroparesis, postoperative ileus, emesis, constipation and colonic pseudo-obstruction, the kit comprising:
a) a first pharmaceutical composition comprising a compound of Formula I, an isomer thereof, a prodrug of said compound or isomer, a pharmaceutically acceptable salt of said compound, isomer or prodrug, or a tautomer thereof, as defined above;
b) a second pharmaceutical composition comprising an additional compound useful for treating a condition selected from the group consisting of gastroesophageal reflux disease, gastroparesis, postoperative ileus, emesis, constipation and colonic pseudo-obstruction; and
c) a container.